On November 25 the National Institutes of Health (NIH) and the Microbicide Trials Network (MTN) announced the discontinuation of an arm of the VOICE study that was evaluating a tenofovir vaginal microbicide, due to lack of effectiveness in an interim analysis.

The benefits of oral and topical antiretroviral drugs for pre-exposure prophylaxis (PrEP) of HIV infection are not fully understood, given conflicting results from several recent studies.

The VOICE trial (Vaginal and Oral Interventions to Control the Epidemic, also known as MTN-003) enrolled more than 5029 sexually active HIV negative women at 15 sites in South Africa, Uganda, and Zimbabwe starting in 2009. Participants were randomly allocated to 5 treatment arms, receiving oral tenofovir (Viread) alone, oral tenofovir plus emtricitabine (Truvada), a placebo tablet, a 1% tenofovir vaginal gel, or a placebo gel, all administered daily.

As previously reported, VOICE investigators halted the oral tenofovir monotherapy arm in September, after an interim analysis found that the study would be unable to demonstrate that it reduced the risk of HIV infection more than placebo.

Last week researchers stopped the tenofovir and placebo gel arms as well, again after an interim analysis by an independent data and safety monitoring board (DSMB) showed that the active gel was not more effective than placebo gel, with an infection rate of 6% in both arms.

The DSMB did not identify any safety concerns with either the oral or gel tenofovir formulations. Women using either gel product will stop doing so and will receive a final evaluation 8 weeks later.

The VOICE study is ongoing and remains blinded with a reduced patient population, now comparing only the oral tenofovir/emtricitabine coformulation versus placebo. Follow-up for all VOICE participants is expected to be completed by June 2012, with final results anticipated in early 2013, according to the NIH.

"This is truly disappointing news -- disappointing for all those who strive to develop tools for HIV prevention, and most of all, for women around the world, particularly those most vulnerable to HIV," said Global Campaign for Microbicides director Yasmin Halima. "It’s not the answer we had hoped for, but it will provide more information to help us better understand what may or may not work."

Conflicting Findings

These findings are in conflict with those of the CAPRISA 004 trial in South Africa -- reported with much fanfare at the 2010 International AIDS Conference -- which showed that 1% tenofovir gel applied vaginally before and after sex (rather than every day) reduced the risk of HIV infection by 39% overall and by 54% among women with good adherence.

The iPrEx study of gay and bisexual men in several countries, and the TDF2 trial of heterosexual women and men in Botswana, both showed that daily oral tenofovir/emtricitabine -- the remaining intervention in the VOICE study -- significantly reduced the risk of HIV infection when given along with risk-reduction counseling, free condoms, and other prevention services.

In iPrEx HIV incidence fell by 42% overall, by 73% among participants who reported good adherence, and by 92% among people who had measurable levels of the drugs in their blood. In TDF2 new infections were reduced by 63% overall and by 78% during the period when the drugs were most likely to be active (within 30 days of their last medication visit).

In contrast, the FEM-PrEP trial did not find a prevention benefit of daily oral tenofovir/emtricitabine for heterosexual women in Kenya, South Africa, and Tanzania; that trial was halted in April after an interim review revealed a similar number of new HIV infections in the tenofovir/emtricitabine and placebo arms.

On the other hand, the Partners PrEP trial of serodiscordant heterosexual couples found that both daily oral tenofovir alone and daily oral tenofovir/emtricitabine combination reduced the risk of infection, by 62% and 73%, respectively.

The reasons for these divergent results are not yet clear. Overall, data suggest tenofovir-based PrEP may work somewhat better for men than for women, but some studies find that women benefit as well. The VOICE results to date indicate that tenofovir/emtricitabine may be more effective than tenofovir alone, given that the oral combination arm has been allowed to continue.

According to MTN, a new Phase 3 trial called FACTS 001 is testing the same 1% tenofovir gel used in CAPRISA 004; this study, which will include approximately 2200 women in South Africa, began enrollment in October and results are expected in 2014.

"This is a blow to the HIV prevention field but is not the definitive answer about whether 1% tenofovir gel is an effective HIV prevention product for women," said AVAC executive director Mitchell Warren. "Based on the limited information available at this time, we simply don’t know whether the lack of effect was due to biology, adherence, both, or something else. This is one reason why the ongoing FACTS 001 trial, which is evaluating a different dosing strategy, with different adherence requirements, should continue...The concept of antiretroviral-based prevention has been proven, but to meet the prevention needs of different populations we need the right drug at the right time in the right place."